Evaluation of the Ankylosing Spondylitis Transcriptome for Oxidative Phosphorylation Pathway: The Shared Pathway with Neurodegenerative Diseases
Abstract
Ankylosing spondylitis (AS) is a systemic inflammatory disorder of joints and entheses. Recent studies have reported an increased prevalence of dementia in AS patients. However, data for exploring the association between dementia and AS remain uncertain.
In this study, enriched pathways and differentially expressed genes (DEGs) were identified in whole blood transcription data of AS patients obtained from the gene expression omnibus (GEO) database; using gene set enrichment analysis (GSEA) and differential expression analysis.
Four pathways, including oxidative phosphorylation, Alzheimer’s, Parkinson’s, and Huntington’s diseases were significantly enriched in AS patients compared to the controls. We identified 22 common genes among the pathways that showed an increasing trend in AS compared to the controls. Five of them including COX7B, NDUFB3, ATP5PF, UQCRB, and NDUFS4 were the most significant genes which were selected for gene expression analysis; using real-time PCR on RNA contents of peripheral blood mononuclear cells (PBMCs) of AS patients and controls (20 samples from each group). The gene expression analysis indicated considerable overexpression of COX7B (p<0.0001) and ATP5J (p=0.0001) genes in AS patients group in comparison to the control samples.
The role of oxidative phosphorylation has previously been established in dementia pathogenesis. Given that AS patients have also a remarkably higher prevalence of dementia than the their healthy counterparts, hence our results may propose that the common pathway of oxidative phosphorylation can be regarded as a possible shared contributing factor in the etiopathogenesis of AS and dementia.
2. Mahmoudi M, Aslani S, Nicknam MH, Karami J, Jamshidi AR. New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications. Mod Rheumatol. 2017;27(2):198-209.
3. Tam L-S, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol. 2010;6(7):399-405.
4. Karami J, Mahmoudi M, Amirzargar A, Gharshasbi M, Jamshidi A, Aslani S, et al. Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients. Genes Immun. 2017;18(3):170-5.
5. Haywood KL, Garratt AM, Dawes PT. Patient-assessed health in ankylosing spondylitis: a structured review. Rheumatology (Oxford). 2005;44(5):577-86.
6. McVeigh CM, Cairns AP. Diagnosis and management of ankylosing spondylitis. Bmj. 2006;333(7568):581-5.
7. Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: current insights. Curr Rheumatol Rep. 2012;14(5):415-21.
8. Jang HD, Park JS, Kim DW, Han K, Shin BJ, Lee JC, et al. Relationship between dementia and ankylosing spondylitis: A nationwide, population-based, retrospective longitudinal cohort study. PloS one. 2019;14(1):e0210335.
9. Jung SY, Park MC, Park YB, Lee SK. Serum amyloid a as a useful indicator of disease activity in patients with ankylosing spondylitis. Yonsei Med J. 2007;48(2):218-24.
10. Kivimäki M, Shipley MJ, Batty GD, Hamer M, Akbaraly TN, Kumari M, et al. Long-term inflammation increases risk of common mental disorder: a cohort study. Mol Psychiatry. 2014;19(2):149-50.
11. Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, et al. Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch Gen Psychiatry. 2008;65(5):542-50.
12. Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N. Pathogenesis of ankylosing spondylitis - recent advances and future directions. Nat Rev Rheumatol. 2017;13(6):359-67.
13. Vanaki N, Aslani S, Jamshidi A, Mahmoudi M. Role of innate immune system in the pathogenesis of ankylosing spondylitis. Biomed Pharmacother. 2018;105:130-43.
14. Pimentel-Santos FM, Ligeiro D, Matos M, Mourão AF, Costa J, Santos H, et al. Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects. Arthritis Res Ther. 2011;13(2):R57.
15. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(43):15545-50.
16. Suárez-Fariñas M, Lowes MA, Zaba LC, Krueger JG. Evaluation of the psoriasis transcriptome across different studies by gene set enrichment analysis (GSEA). PloS one. 2010;5(4):e10247.
17. Team RC. R: A language and environment for statistical computing. 2013.
18. Wettenhall JM, Smyth GK. limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics. 2004;20(18):3705-6.
19. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8.
20. Rahmani F, Asgharzadeh F, Avan A, Barneh F, Parizadeh MR, Ferns GA, et al. Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-κB signaling pathways. Life Sci. 2020;249:117470.
21. Ligges U, Mächler M. Scatterplot3d-an r package for visualizing multivariate data. Technical Report, 2002.
22. Biesbroek PS, Heslinga SC, Konings TC, van der Horst-Bruinsma IE, Hofman MBM, van de Ven PM, et al. Insights into cardiac involvement in ankylosing spondylitis from cardiovascular magnetic resonance. Heart. 2017;103(10):745-52.
23. Martindale J, Smith J, Sutton CJ, Grennan D, Goodacre L, Goodacre JA. Disease and psychological status in ankylosing spondylitis. Rheumatology (Oxford). 2006;45(10):1288-93.
24. Li Y, Zhang S, Zhu J, Du X, Huang F. Sleep disturbances are associated with increased pain, disease activity, depression, and anxiety in ankylosing spondylitis: a case-control study. Arthritis Res Ther. 2012;14(5):R215.
25. Lin CS, Liu LT, Ou LH, Pan SC, Lin CI, Wei YH. Role of mitochondrial function in the invasiveness of human colon cancer cells. Oncol Rep. 2018;39(1):316-30.
26. Ohnishi T, Ohnishi ST, Salerno JC. Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I). Biol Chem. 2018; 399(11):1249-64.
27. Alston CL, Howard C, Oláhová M, Hardy SA, He L, Murray PG, et al. A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype. J Med Genet. 2016;53(9):634-41.
28. Hroudová J, Singh N, Fišar Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease. Biomed Res Int. 2014;2014:175062.
29. Zhang L, Guo XQ, Chu JF, Zhang X, Yan ZR, Li YZ. Potential hippocampal genes and pathways involved in Alzheimer's disease: a bioinformatic analysis. Genet Mol Res. 2015;14(2):7218-32.
30. Manczak M, Park BS, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147-62.
31. Sadlock JE, Lightowlers RN, Capaldi RA, Schon EA. Isolation of a cDNA specifying subunit VIIb of human cytochrome c oxidase. Biochim Biophys Acta. 1993;1172(1-2):223-5.
32. Fornuskova D, Stiburek L, Wenchich L, Vinsova K, Hansikova H, Zeman J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J. 2010;428(3):363-74.
33. Diaz F. Cytochrome c oxidase deficiency: patients and animal models. Biochim Biophys Acta. 2010;1802(1):100-10.
34. Gnaiger E, Lassnig B, Kuznetsov A, Rieger G, Margreiter R. Mitochondrial oxygen affinity, respiratory flux control and excess capacity of cytochrome c oxidase. J Exp Biol. 1998;201(Pt 8):1129-39.
35. Stiburek L, Hansikova H, Tesarova M, Cerna L, Zeman J. Biogenesis of eukaryotic cytochrome c oxidase. Physiol Res. 2006;55 Suppl 2:S27-41.
36. Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet. 2012;91(5):942-9.
37. Nagai Y, Ogasawara A, Heese K. [Possible mechanisms of A beta(1-40)- or A beta(1-42)-induced cell death and their rescue factors]. Nihon Yakurigaku Zasshi. 2004;124(3):135-43.
38. Bai B, Xie B, Pan Z, Shan L, Zhao J, Zhu H. Identification of candidate genes and long non-coding RNAs associated with the effect of ATP5J in colorectal cancer. Int J Oncol. 2018;52(4):1129-38.
39. Javed AA, Ogata K, Sanadi DR. Human mitochondrial ATP synthase: cloning cDNA for the nuclear-encoded precursor of coupling factor 6. Gene. 1991;97(2):307-10.
40. Osanai T, Tanaka M, Magota K, Tomita H, Okumura K. Coupling factor 6-induced activation of ecto-F1F(o) complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice. Diabetologia. 2012;55(2):520-9.
41. Chai SB, Hui YM, Li XM, Tang CS. Plasma level of mitochondrial coupling factor 6 increases in patients with coronary heart disease. Circ J. 2007;71(5):693-7.
42. Osanai T, Nakamura M, Sasaki S, Tomita H, Saitoh M, Osawa H, et al. Plasma concentration of coupling factor 6 and cardiovascular events in patients with end-stage renal disease. Kidney Int. 2003;64(6):2291-7.
43. Zhu H, Chen L, Zhou W, Huang Z, Hu J, Dai S, et al. Over-expression of the ATP5J gene correlates with cell migration and 5-fluorouracil sensitivity in colorectal cancer. PloS one. 2013;8(10):e76846.
44. Ozkan Y. Cardiac Involvement in Ankylosing Spondylitis. J Clin Med Res. 2016;8(6):427-30.
45. Charalabopoulos K, Charalabopoulos A, Papaioannides D. Diabetes mellitus type I associated with dermatomyositis: an extraordinary rare case with a brief literature review. BMJ Case Rep. 2009;2009.
46. Chang CC, Chang CW, Nguyen PA, Chang TH, Shih YL, Chang WY, et al. Ankylosing spondylitis and the risk of cancer. Oncol Lett. 2017;14(2):1315-22.
47. Kuksal N, Chalker J, Mailloux RJ. Progress in understanding the molecular oxygen paradox - function of mitochondrial reactive oxygen species in cell signaling. Biol Chem. 2017;398(11):1209-27.
48. Karakoc M, Altindag O, Keles H, Soran N, Selek S. Serum oxidative-antioxidative status in patients with ankylosing spondilitis. Rheumatol Int. 2007;27(12):1131-4.
49. Hoffmann MH, Griffiths HR. The dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: evidence from preclinical models. Free Radic Biol Med. 2018;125:62-71.
50. Lahiri A, Lahiri A, Das P, Vani J, Shaila MS, Chakravortty D. TLR 9 activation in dendritic cells enhances salmonella killing and antigen presentation via involvement of the reactive oxygen species. PloS one. 2010;5(10):e13772.
51. Ryan BJ, Nissim A, Winyard PG. Oxidative post-translational modifications and their involvement in the pathogenesis of autoimmune diseases. Redox Biol. 2014;2:715-24.
52. Puccetti A, Dolcino M, Tinazzi E, Moretta F, D'Angelo S, Olivieri I, et al. Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are Present in Ankylosing Spondylitis. PloS one. 2017;12(1):e0171073.
53. Hoffmann MH, Griffiths HR. The dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: evidence from preclinical models. Free Radical Biology and Medicine. 2018;125:62-71.
54. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221.
55. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221-5.
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Issue | Vol 20 No 5 (2021) | |
Section | Original Article(s) | |
DOI | https://doi.org/10.18502/ijaai.v20i5.7406 | |
Keywords | ||
Ankylosing spondylitis Dementia Gene expression Oxidative phosphorylation |
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